Multiple Sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS) and results in neurological and clinical disability i number of adults in the US. Leukocyte infiltration and plaques of demyelination in the brain and spinal cord of patients are a hallmark of MS. Currently, there is no cure and few therapies for this debilitating disease. The disease is being primarily managed with the help of immuno- modulators with varying degree of effectiveness and almost all having significant side-effects. Reducing leukocyte infiltration is highly beneficial and decreases the severity and disease pathogenesis. However, such blocking therapies have also shown unexpected side effects, including cases of PML in several patients, suggesting that a novel approach is desirable. The leukocytic adhesion receptor integrin CD11b/CD18 (Mac- 1, M2) is central to the various biological functions of these cells. CD11b/CD18 is also a well-established target in MS. Since the prior approaches using antibodies and ligand mimics to block the function of CD11b/CD18 (anti-adhesion therapy) failed in several clinical trials, we pursued an alternative approach for reducing leukocyte migration and infiltration that involves enhancing cell adhesion rather than blocking it. Adhaere Pharmaceuticals, Inc. (Adhaere) has developed novel CD11b/CD18 small molecule agonists that bind to CD11b/CD18 and enhance CD11b/CD18-mediated cell adhesion. While counter-intuitive, increasing cell adhesion reduces leukocyte migration and decreases their trafficking in vivo. Adhaere's compounds (termed leukadherins) show high selectivity for CD11b/CD18 and high efficacy in multiple experimental models of inflammatory injury, including the EAE model of MS. Therefore, these compounds are promising new therapeutic candidates for treating MS in human patients. However, the lead compounds show low micromolar potency, poor aqueous solubility and, thus, need some chemical/structural optimization. Additionally, the lead central scaffold contains a thiazolidine-one motif, which can easily be modified to further improve the potency and bioavailability of the lead compounds. The overall goal of this proposal is to chemically refine and fully develop this family of first-in class lead molecules. The optimized compounds will be tested in in vitro ADME-T assays prior to their in vivo PK and efficacy evaluations. Our long-term goal is to develop these leads into FDA-regulated, pharmacologically useful drug candidates for treating MS in humans. The studies proposed here will lead to the development of novel therapeutic agents for treating MS in humans.